1. Field of the Invention
This invention relates to the transdermal administration of effective dose levels of buprenorphine to patients. More particularly, it relates to transdermal dosage forms for buprenorphine and to their use.
2. Prior Art
Buprenorphine is the common name for (5.alpha., 7.alpha. (s))-17-cyclopropylmethyl)-.alpha.-(1,1-dimethylethyl)-4,5-epoxy-18,19-dih ydro-3-hydroxy-6-methoxy-.alpha.-methyl-6,14-ethenomorphinan-7-methanol. This material is sold under the trademarks Buprenex (Morton-Norwich) and Tengesic (Reckitt and Coleman). It is described in U.S. Pat. No. 3,433,791 (1968). It is an analgesic which demonstrates narcotic agonist-antagonist properties. It has been used principally for the management of pain associated with surgical procedures, cancer, accidental trauma, and myocardial infarction. Buprenorphine is also being used in the detoxification treatment of heroin addicts due to its narcotic agonist/antagonist properties. Bickel, W. K., et al., Chem. Pharmacol. Ther. (1988)43:1:72-78 and Fudala, P. J., et al., Clin. Pharmacol. Ther. (1990)47:4:525-534.
Heretofore, buprenorphine has been administered most commonly by intramuscular injection or intravenous injection as reported by Norwich Eaton Pharmaceuticals, Inc., in "Buprenex Prescribing Information," Norwich, N.Y., 1986; "Buprenex Compatibility Chart," Norwich, N.Y., 1986; and "Buprenex: Background Data for Review for Pharmacy and Therapeutic Committees," Norwich, N.Y., May 1985. See also, Heel, R. C., et al., "Buprenorphine : A Review of Its Pharmacological Properties and Therapeutic Efficacy," Drugs (1979) 17:81-110.
In view of the chronic nature of many of the severe conditions for which buprenorphine is employed, it can often be desired to administer this drug over a prolonged period of time. To that end, the Norwich Eaton publications mention the possibility of slow, prolonged IV administration and Robbie, D. S., has published the results of a trial of sublingual buprenorphine in chronic cancer pain settings in British J. Clin. Pharmacol. (1979) 33:587-90. Additional discussions of sublingual administration of buprenorphine include: Bullingham, R., et al., Clin. Pharmcol. Ther. (1980) 28:667-72; Bullingham, R., et al., Clin. Pharmacol. (1983) 8:332-43; Bullingham, R., et al., British Clin. Pharmacol. (1982) 13:665-73; Rosana, C., et al., Clin. Ther. (1982) 5:61-8; O'Sullivan, G. H., et al., Anaesthesia (1983) 38:977-84; and Adriensen, H., et al, Acta. Anaesthesia Belg. (1985) 36:33-40.
The possibility of transdermal administration of buprenorphine has also been postulated. PCT published Patent Application No. WO88/09676 (Warner Lambert, published 15 Dec. 1988) is directed to the use of fatty acids or fatty acid esters as transdermal drug delivery enhancers and mentions buprenorphine as one of the drugs with which these enhancers might be used. A similar suggestion may be found in U.S. Pat. No. 4,626,539, issued 2 Dec. 1986 to B. Aungst, et al. European Patent Application No. 0,282,156 (Alza Corp., 14 Sept. 1988) teaches that transdermal coadministration of corticosteroids with irritating drugs is advantageous and lists buprenorphine as a drug which might benefit from such coadministration. PCT Patent Application WO88/01497 (Rutgers, The State University of New Jersey, 10 Mar. 1988) and the corresponding U.S. Patent No. 4,806,341, issued Feb. 21, 1989, are directed to a transdermal morphinan narcotic analgesic or antagonist dosage unit and propose buprenophine as a possible drug for inclusion. With the possible exception of the WO88/01497 reference and its United States counterpart, which include a pro forma hypothetical example to a buprenophine transdermal system, none of these references has any examples which actually purport to demonstrate transdermal administration of buprenophine and no data relating to the flux of buprenophine through the skin are provided. Therefore, at best, this art is a speculative teaching that leaves the reader with the task of experimenting to find out whether or not it is possible to administer buprenophine transdermally in vivo at therapeutically effective rates.